Tazemetostat (EPZ6438; E-7438)

Description: Tazemetostat (formerly known as EPZ-6438 or E7438) is an orally bioavailable, potent, and selective EZH2 (Enhancer of Zeste-Homolog 2) inhibitor with antineoplastic activity. It inhibits EZH2 with Ki and IC50 of 2.5 nM and 11 nM in cell-free assays. Mutations within the catalytic domain of the histone methyltransferase EZH2 have been identified in subsets of patients with non-Hodgkin lymphoma (NHL). These genetic alterations are hypothesized to confer an oncogenic dependency on EZH2 enzymatic activity in these cancers. Tazemetostat exhibits a 35-fold selectivity versus EZH1 and > 4, 500-fold selectivity relative to 14 other HMTs.Tazemetostat competitively binds to the S-adenosylmethionine (SAM) binding site of EZH2 and also non-competitively binds to the binding sites of peptide or nucleosome substrate. Tazemetostat selectively inhibits EZH2 with selectivity 35-fold greater than EZH1. Study results have suggested that Tazemetostat exhibits dramatic and permanent anti-tumor activity in MRT models through synergistic effects of Tazemetostat-mediated EZH2 inhibition on several cancer pathways.

References: Proc Natl Acad Sci U S A. 2013 May 7; 110(19):7922-7

Tazemetostat; E7-438; E 7438; E7438; EPZ 6438; EPZ6438; EPZ-6438;

Chemical Name: N-((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1, 1'-biphenyl]-3-carboxamide

SMILES Code: O=C(C1=CC(C2=CC=C(CN3CCOCC3)C=C2)=CC(N(CC)C4CCOCC4)=C1C)NCC5=C(C)C=C(C)NC5=O